Department of Nephrology, West China Hospital of Sichuan University, Chengdu, People's Republic of China.
Diabetologia. 2011 Oct;54(10):2713-23. doi: 10.1007/s00125-011-2237-y. Epub 2011 Jul 9.
AIMS/HYPOTHESIS: Although C-reactive protein (CRP) has been implicated as a risk factor in diabetes, its pathogenic importance in diabetic kidney disease (DKD) remains unclear. The present study investigated the potential role of CRP in DKD.
Diabetes was induced by streptozotocin in human CRP transgenic and wild-type mice for assessment of kidney injury at 24 weeks by real-time PCR, immunohistochemistry and western blot analysis. In vitro, the pathogenic effect of CRP was investigated using human kidney tubular epithelial cells cultured with high glucose and/or CRP.
We found that CRP transgenic mice developed much more severe diabetic kidney injury than wild-type mice, as indicated by a significant increase in urinary albumin excretion and kidney injury molecule-1 abundance, enhanced infiltration of macrophages and T cells, and upregulation of pro-inflammatory cytokines (IL-1β, TNFα) and extracellular matrix (collagen I, III and IV). Enhanced renal inflammation and fibrosis in CRP transgenic mice was associated with upregulation of CRP receptor, CD32a, and over-activation of the TGF-β/SMAD and nuclear factor κB signalling pathways. In vitro, CRP significantly upregulated pro-inflammatory cytokines (IL-1β, TNFα, monocyte chemoattractant protein-1 [MCP-1]) and pro-fibrotic growth factors (TGF-β1, connective tissue growth factor [CTGF]) via CD32a/64. CRP was induced by high glucose, which synergistically promoted high glucose-mediated renal inflammation and fibrosis.
CONCLUSIONS/INTERPRETATION: CRP is not only a biomarker, but also a mediator in DKD. Enhanced activation of TGF-β/SMAD and nuclear factor κB signalling pathways may be the mechanisms by which CRP promotes renal inflammation and fibrosis under diabetic conditions.
目的/假设：虽然 C 反应蛋白（CRP）已被认为是糖尿病的危险因素，但它在糖尿病肾病（DKD）中的致病作用仍不清楚。本研究旨在探讨 CRP 在 DKD 中的潜在作用。
链脲佐菌素诱导糖尿病，通过实时 PCR、免疫组织化学和 Western blot 分析在 24 周时评估肾脏损伤。在体外，通过高糖和/或 CRP 培养人肾小管上皮细胞，研究 CRP 的致病作用。
我们发现 CRP 转基因小鼠比野生型小鼠发生更严重的糖尿病肾病损伤，表现为尿白蛋白排泄和肾损伤分子-1 丰度显著增加，巨噬细胞和 T 细胞浸润增强，促炎细胞因子（IL-1β、TNFα）和细胞外基质（胶原 I、III 和 IV）上调。CRP 转基因小鼠肾脏炎症和纤维化增强与 CRP 受体 CD32a 上调和 TGF-β/SMAD 和核因子κB 信号通路过度激活有关。在体外，CRP 通过 CD32a/64 显著上调促炎细胞因子（IL-1β、TNFα、单核细胞趋化蛋白-1[MCP-1]）和促纤维化生长因子（TGF-β1、结缔组织生长因子[CTGF]）。CRP 由高糖诱导，协同促进高糖介导的肾脏炎症和纤维化。
结论/解释：CRP 不仅是一种生物标志物，也是 DKD 的一种介质。在糖尿病条件下，TGF-β/SMAD 和核因子κB 信号通路的过度激活可能是 CRP 促进肾脏炎症和纤维化的机制。
